Malaria is a leading cause of morbidity and mortality in children in sub-Saharan Africa, causing >1 million deaths annually. Our studies at Mulago Hospital, Kampala, Uganda document that 21.6% of children >5 years of age who survive CM have cognitive deficits 6 months after hospitalization. However, the effects of CM on cognition in younger children have not been prospectively characterized, and the underlying question of what leads to cognitive deficits in children with CM remains unanswered. The central hypothesis of this study is that specific immunologic/inflammatory and genetic factors lead to cognitive and neurologic deficits in a subset of children with CM. Our specific aims are to: 1) Establish the areas, frequency and severity of cognitive and neurologic function affected by cerebral malaria in children of different ages (18 months-4 years, 5-12 years). We will compare areas, frequency and age-adjusted levels of cognitive and neurologic deficits in children with CM in 2 age groups (18 mo-4 years, 5-12 years) to healthy children and children with severe malarial anemia in these age groups, at discharge and in follow-up. Cognitive function in the areas of attention, reasoning, memory, motor function and language will be assessed. 2) Identify the immunologic/inflammatory and genetic factors associated with cognitive and neurologic deficits in children with cerebral malaria.We will compare the presence/level of specific risk factors in children with CM age 18 months-12 years to the presence/level of cognitive and neurologic deficits at discharge and in follow-up. To test that the genetic and plasma/ leukocyte inflammatory factors are specific for CM, they will also be assessed in children with severe malarial anemia (without CNS involvement) and in community controls. We will assess: a) markers of the components of endovascular inflammation (e.g. plasma levels of VCAM-1. ICAM-1, endothelial microparticles, endothelin-1, reactive oxygen (ROS) and nitrogen (RNS) species, and pro- and anti- inflammatory cytokines, and leukocyte heme oxygenase-1 (HO-1) expression; b) markers of central nervous system inflammation (e.g., CSF levels of ROS and RNS, pro- and anti-inflammatory cytokines, quinolinic and kynurenic acid, and tau and neuron- specific enolase),; and c) genetic polymorphisms in apolipoprotein-E and HO-1, which may affect cognition through alterations in CNS immune responses. We expect that this study will constitute a major advance in the knowledge of CM pathogenesis and long-term outcomes, and will lead to clinical trials of interventions to prevent cognitive and neurologic sequelae in children with CM. We also expect this study will provide insights and hypothesis generating information for researchers involved in investigating the many other types of non- traumatic brain injury and recovery in the developed and developing world. PUBLIC HEALTH RELEVANCE: The present study will assess how frequently children develop cognitive impairment after cerebral malaria, and what factors might lead to this impairment. We believe that our study findings will be the first step in developing interventions to prevent the brain injury that causes cognitive impairment. The study therefore has the potential to lead to the prevention of brain injury in hundreds of thousands of children in sub-Saharan Africa.